My career goal is to use clinical and translational research to improve the health of HIV-infected individuals on antiretroviral therapy (ART) by reducing the rates of HIV-associated non-AIDS conditions, in particular fragility fractures. Antiretroviral therapy (ART) suppresses HIV replication and prevents AIDS-related sequelae. Nevertheless, patients with well-controlled HIV are still not fully restored to health and exhibit features characteristic of the elderly, including increased rates of osteoporosis and associated fragility fractures, atherosclerosis, frailty, and cognitive impairment. While the rates of the othr age-associated comorbidities appear to decrease with ART, bone loss is unique in that it accelerates after ART initiation, at least for the short term. Fragility fractures not only dramatically increases an individual's rate of institutionalization but also the risk of death. My research will help define the underlying causes and appropriate clinical management of ART-associated bone mineral density (BMD) loss in HIV. My central hypothesis is that BMD loss in ART-treated HIV-infected individuals is due in part to the effects of ART (and/or HIV) and ART-associated immune reconstitution and that incorporating HIV-specific and treatment-related factors into a prediction tool will allow for improved identification of those most at risk for on-RT bone loss. I propose the following Specific Aims: 1) Determine the extent of BMD loss in long-term ART-treated HIV-infected individuals compared to uninfected individuals; 2) Determine the relationship between baseline and on-ART levels of T cell activation and ART-associated bone loss; and 3) Determine the contribution of HIV-specific and ART treatment factors to ART-associated bone loss and osteoporosis. We will enroll a prospective clinical study through the AIDS Clinical Trials Group (ACTG) where dual energy X-ray absorptiometry (DXA) will be performed in ART-treated HIV-infected participants who had previous serial DXA a median of seven years prior. BMD changes in these HIV-infected individuals will be compared at the patient level to BMD changes found in uninfected men and women from two comparator cohorts. We will perform a nested case-control study to determine immunologic correlates of bone loss in HIV. Results from the Aim 1 and 2 will inform my work in Aim 3 where I will develop and validate prediction rules for both bone loss (all ages) and osteoporosis (for those over age 50) using clinical trials and observational datasets, and by enrolling a prospective study at Stanford. The expected contribution of the proposed research is to advance the clinical and mechanistic understanding of bone disease in HIV, allowing for interventions to reduce fractures. The proposed studies will also provide insights into bone disease in other chronic inflammatory conditions and the effect of immune aging on bone loss. To develop the skills for the proposed research and achieve my career goals, I will take courses and attend seminars in metabolic bone disease, translational immunology, and biostatistics. I will also greatly benefit from my mentoring team providing structured guidance in their respective areas of expertise: 1) Dr. Zolopa (primary mentor) in epidemiological analyses, conduct of responsible research, development and implementation of an integrated research agenda, career networking, and NIH grant writing 2) Dr. Brown (co-mentor) in metabolic bone disease and NIH grant writing, 3) Dr. Desai (co-mentor) in biostatistics; 4) Dr. Goronzy (consultant) in translational immunology; and 5) Dr. Wu (consultant) in osteoporosis and osteoimmunology. I have unique access to resources available at Stanford University and through the ACTG that will allow me to accomplish the proposed training and research plan. After the award period with a better understanding of the clinical and mechanistic aspects of bone loss in HIV, I will be poised to gain R01 support to evaluate interventions to reduce ART-associated bone loss and fractures.